tbuckley/cabot-search huggingface dataset:
SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models
Authors: Elizabeth Gray, Michelle Ulrich, Angela Epp, Patrick Younan, Disha Sahetya, Kelly Hensley, Sean Allred, Li-Ya Huang, Julie Hahn, Kristen Gahnberg, Piper M Treuting, Esther S Trueblood, John J Gosink, Robert Thurman, Serena Wo, Kellie Spahr, Evgenia Jane Haass, Katie Snead, Dannah Miller, Mary Padilla, Alyson J Smith, Chris Frantz, Jason P Schrum, Natalya Nazarenko, Shyra J Gardai
Journal: Journal for ImmunoTherapy of Cancer (2023)

SGN-B7H4V is a novel investigational vedotin antibody-drug conjugate (ADC) comprising a B7-H4-directed human monoclonal antibody conjugated to the cytotoxic payload monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine citrulline (mc-vc) linker. This vedotin linker-payload system has been clinically validated in multiple Food and Drug Administration approved agents including brentuximab vedotin, enfortumab vedotin, and tisotumab vedotin. B7-H4 is an immune checkpoint ligand with elevated expression on a variety of solid tumors, including breast, ovarian, and endometrial tumors, and limited normal tissue expression. SGN-B7H4V is designed to induce direct cytotoxicity against target cells by binding to B7-H4 on the surface of target cells and releasing the cytotoxic payload MMAE upon internalization of the B7-H4/ADC complex.B7-H4 expression was characterized by immunohistochemistry across multiple solid tumor types. The ability of SGN-B7H4V to kill B7-H4-expressing tumor cells in vitro and in vivo in a variety of xenograft tumor models was also evaluated. Finally, the antitumor activity of SGN-B7H4V as monotherapy and in combination with an anti-programmed cell death-1 (PD-1) agent was evaluated using an immunocompetent murine B7-H4-expressing Renca tumor model.Immunohistochemistry confirmed B7-H4 expression across multiple solid tumors, with the highest prevalence in breast, endometrial, and ovarian tumors. In vitro, SGN-B7H4V killed B7-H4-expressing tumor cells by MMAE-mediated direct cytotoxicity and antibody-mediated effector functions including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. In vivo, SGN-B7H4V demonstrated strong antitumor activity in multiple xenograft models of breast and ovarian cancer, including xenograft tumors with heterogeneous B7-H4 expression, consistent with the ability of vedotin ADCs to elicit a bystander effect. In an immunocompetent murine B7-H4-expressing tumor model, SGN-B7H4V drove robust antitumor activity as a monotherapy that was enhanced when combined with an anti-PD-1 agent.The immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors. SGN-B7H4V demonstrates robust antitumor activity in preclinical models through multiple potential mechanisms. Altogether, these preclinical data support the evaluation of SGN-B7H4V as a monotherapy in the ongoing phase 1 study of SGN-B7H4V in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies.
PD-1 blockade in combination with dasatinib potentiates induction of anti-acute lymphocytic leukemia immunity
Authors: Paul Koller, Natalia Baran, Karine Harutyunyan, Antonio Cavazos, Saradhi Mallampati, Renee L Chin, Zhou Jiang, Xian Sun, Heng-Huan Lee, Jennifer L Hsu, Patrick Williams, Xuelin Huang, Michael A Curran, Mien-Chie Hung, Marina Konopleva
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism of immune escape in patients with acute myeloid leukemia after HSCT. Here we report that treatment with the tyrosine kinase inhibitor, dasatinib, and an anti-PD-1 antibody in preclinical models of Philadelphia chromosome positive B-cell acute lymphoblastic leukemia is highly active. The dasatinib and anti-PD-1 combination reduces tumor burden, is efficacious, and extends survival. Mechanistically, we found that treatment with dasatinib significantly increased MHC II expression on the surface of antigen-presenting cells (APC) in a tumor microenvironment-independent fashion and caused influx of APC cells into the leukemic bone marrow. Finally, the induction of MHC II may potentiate immune memory by impairing leukemic engraftment in mice previously cured with dasatinib, after re-inoculation of leukemia cells. In summary, our data suggests that anti-PD-1 therapy may enhance the killing ability of dasatinib via dasatinib driven APC growth and expansion and upregulation of MHC II expression, leading to antileukemic immune rewiring.
Impact of Undiagnosed Chronic Obstructive Pulmonary Disease and Asthma on Symptoms, Quality of Life, Healthcare Use, and Work Productivity
Authors: Emily Gerstein, Jared Bierbrier, G. Alex Whitmore, Katherine L. Vandemheen, Celine Bergeron, Louis-Philippe Boulet, Andreanne Cote, Stephen K. Field, Erika Penz, R. Andrew McIvor, Catherine Lemière, Samir Gupta, Paul Hernandez, Irvin Mayers, Mohit Bhutani, M. Diane Lougheed, Christopher J. Licskai, Tanweer Azher, Nicole Ezer, Martha Ainslie, Gonzalo G. Alvarez, Sunita Mulpuru, Shawn D. Aaron
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: A significant proportion of individuals with chronic obstructive pulmonary disease (COPD) and asthma remain undiagnosed. Objectives: The objective of this study was to evaluate symptoms, quality of life, healthcare use, and work productivity in subjects with undiagnosed COPD or asthma compared with those previously diagnosed, as well as healthy control subjects. Methods: This multicenter population-based case-finding study randomly recruited adults with respiratory symptoms who had no previous history of diagnosed lung disease from 17 Canadian centers using random digit dialing. Participants who exceeded symptom thresholds on the Asthma Screening Questionnaire or the COPD Diagnostic Questionnaire underwent pre- and post-bronchodilator spirometry to determine if they met diagnostic criteria for COPD or asthma. Two control groups, a healthy group without respiratory symptoms and a symptomatic group with previously diagnosed COPD or asthma, were similarly recruited. Measurements and Main Results: A total of 26,905 symptomatic individuals were interviewed, and 4,272 subjects were eligible. Of these, 2,857 completed pre- and post-bronchodilator spirometry, and 595 (21%) met diagnostic criteria for COPD or asthma. Individuals with undiagnosed COPD or asthma reported greater impact of symptoms on health status and daily activities, worse disease-specific and general quality of life, greater healthcare use, and poorer work productivity than healthy control subjects. Individuals with undiagnosed asthma had symptoms, quality of life, and healthcare use burden similar to those of individuals with previously diagnosed asthma, whereas subjects with undiagnosed COPD were less disabled than those with previously diagnosed COPD. Conclusions: Undiagnosed COPD or asthma imposes important, unmeasured burdens on the healthcare system and is associated with poor health status and negative effects on work productivity.
Discovery of a glucocorticoid receptor (GR) activity signature correlates with immune cell infiltration in adrenocortical carcinoma
Authors: Kan Wu, Zhihong Liu, Jiayu Liang, Yuchun Zhu, Xianding Wang, Xiang Li
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy, of which &gt;40% present with glucocorticoid excess. Glucocorticoids and glucocorticoid receptor (GR) signaling have long been thought to suppress immunity and promote tumor progression by acting on immune cells. Here, we provide new insights into the interaction between GR signaling activity and the immune signature of ACC as a potential explanation for immune escape and resistance to immunotherapy. Methods First, GR immunohistochemical staining and immunofluorescence analysis of tumor-infiltrating lymphocyte (CD4 T, CD8 T cells, natural killer (NK) cells, dendritic cells and macrophages) were performed in 78 primary ACC tissue specimens. Quantitative data of immune cell infiltration in ACC were correlated with clinical characteristics. Second, we discovered a GR activity signature (GRsig) using GR-targeted gene networks derived from global gene expression data of primary ACC. Finally, we identified two GRsig-related subtypes based on the GRsig and assessed the differences in immune characteristics and prognostic stratification between the two subtypes. Results GR was expressed in 90% of the ACC tumors, and CD8+ cytotoxic T lymphocytes were the most common infiltrating cell type in ACC specimens (88%, 8.6 cells/high power field). GR expression positively correlated with CD8+ T cell (Phi=0.342, p&lt;0.001), CD4+ T cell (Phi=0.280, p&lt;0.001), NK cell (Phi=0.280, p&lt;0.001), macrophage (Phi=0.285, p&lt;0.001), and dendritic cell (Phi=0.397, p&lt;0.001) infiltration. Clustering heatmap analysis also displayed high immune cell infiltration in GR high-expressing tumors and low immune cell infiltration in GR-low tumors. High GR expression and high immune cell infiltration were significantly associated with better survival. Glucocorticoid excess is associated with low immune cell abundance and unfavorable prognosis. A GRsig comprizing n=34 GR-associated genes was derived from Gene Expression Omnibus/The Cancer Genome Atlas (TCGA) data sets and used to define two GRsig-related subtypes in the TCGA cohort. We demonstrated distinct differences in the immune landscape and clinical outcomes between the two subtypes. Conclusion GR expression positively correlates with tumor-infiltrating immune cells in ACC. The GRsig could serve as a prognostic biomarker and may be helpful for prognosis prediction and response to immunotherapy. Consequently, targeting the GR signaling pathway might be pivotal and should be investigated in clinical studies.
Deciphering treatment patterns in non-severe/moderate aplastic anemia: an international observational study
Authors: Bruno Fattizzo, Carmelo Gurnari, Giulio Cassanello, Marta Bortolotti, Hussein Awada, Sabrina Giammarco, Dario Consonni, Simona Sica, Shreyans Gandhi, Roochi Trikha, Joanna Large, Sarah Salter, Jaroslaw P. Maciejewski, Wilma Barcellini, Austin G. Kulasekararaj
Journal: Leukemia (2023)

Abstract Non-severe aplastic anemia is a rare bone marrow failure disorder characterized by variable degrees and combination of cytopenias, with limited data on management and outcome. We describe a large multicentric series of 259 patients, focusing on clinical and molecular features, treatment, evolution, and survival. The majority required treatment with cyclosporine (CyA) alone ( N = 84) or in combination with anti-thymocyte globulin (ATG,44) or eltrombopag (20), eltrombopag alone (10), or others (25) including androgens. Similar outcomes were observed across different strategies, with a 6-month overall response rate of 73% for CyA, 74% for ATG plus CyA, 68% for CyA plus eltrombopag, 87% for eltrombopag, and 79% for others. Notably, 56 patients (39%), mainly receiving CyA plus eltrombopag, achieved a trilineage response ( p = 0.02). Progression to myeloid neoplasms was limited (8%) and not related to mutational status. Hemolytic PNH developed in 10% of cases, being predicted by detection of small clones at diagnosis. Survival was negatively impacted by age, male gender, LDH, platelets/erythrocyte transfusion need, and somatic mutations by NGS, and positively by higher neutrophils at diagnosis, PNH clones, and trilineage response at 6 and 12 months. Multivariable analysis confirmed the detrimental role of age and the favorable association with PNH clone and trilineage response at 6 months.
Predicting Adverse Cardiac Events After Radiotherapy for Locally Advanced Non–Small Cell Lung Cancer
Authors: Hyunsoo Joshua No, Felicia B. Guo, Natalie Jung-In Park, Noah Kastelowitz, June-Wha Rhee, Daniel Eugene Clark, Alexander Li-Che Chin, Lucas Kas Vitzthum, Kathleen Claire Horst, Everett James Moding, Billy W. Loo, Maximilian Diehn, Michael Sargent Binkley
Journal: JACC CardioOncology (2023)

Radiotherapy may cause grade ≥3 cardiac events, necessitating a better understanding of risk factors. The potential predictive role of imaging biomarkers with radiotherapy doses for cardiac event occurrence has not been studied.
A protein-free vaccine stimulates innate immunity and protects against nosocomial pathogens
Authors: Jun Yan, Travis B. Nielsen, Peggy Lu, Yuli Talyansky, Matt Slarve, Hernan Reza, Boris Novakovic, Mihai G. Netea, Ashley E. Keller, Troy Warren, Antonio DiGiandomenico, Bret R. Sellman, Brian M. Luna, Brad Spellberg
Journal: Science Translational Medicine (2023)

Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care–associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan that improved survival and reduced bacterial burden of mice with invasive blood or lung infections caused by methicillin-resistant Staphylococcus aureus , vancomycin-resistant Enterococcus faecalis , extended-spectrum beta-lactamase–expressing Escherichia coli , and carbapenem-resistant strains of Acinetobacter baumannii , Klebsiella pneumoniae , and Pseudomonas aeruginosa. The vaccine also conferred protection against the fungi Rhizopus delemar and Candida albicans . Efficacy was apparent by 24 hours and lasted for up to 28 days after a single vaccine dose, with a second dose restoring efficacy. The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant health care–associated infections.
Non-invasive PD-L1 quantification using [<sup>18</sup>F]DK222-PET imaging in cancer immunotherapy
Authors: Akhilesh Mishra, Kuldeep Gupta, Dhiraj Kumar, Gabriela Lofland, Ajay Kumar Sharma, Lilja B Solnes, Steven P Rowe, Patrick M Forde, Martin G Pomper, Edward W Gabrielson, Sridhar Nimmagadda
Journal: Journal for ImmunoTherapy of Cancer (2023)

Combination therapies that aim to improve the clinical efficacy to immune checkpoint inhibitors have led to the need for non-invasive and early pharmacodynamic biomarkers. Positron emission tomography (PET) is a promising non-invasive approach to monitoring target dynamics, and programmed death-ligand 1 (PD-L1) expression is a central component in cancer immunotherapy strategies. [
Safety and Performance of the Aortix Device in Acute Decompensated Heart Failure and Cardiorenal Syndrome
Authors: Jennifer A. Cowger, Mir B. Basir, David A. Baran, Christopher S. Hayward, Janani Rangaswami, Antony Walton, Cristina Tita, Steven Minear, Emad Hakemi, Liviu Klein, Richard Cheng, Robby Wu, Bibhu D. Mohanty, Jason J. Heuring, Elisabeth Neely, Palak Shah
Journal: JACC Heart Failure (2023)

Cardiorenal syndrome (CRS) complicates 33% of acute decompensated heart failure (ADHF) admissions, and patients with persistent congestion at discharge have high 30-day event rates. The purpose of this study was to evaluate a novel catheter-deployed intra-aortic entrainment pump (IAEP) in patients with ADHF with CRS and persistent congestion. A multicenter (n = 14), nonrandomized, single-arm, safety and feasibility study of IAEP therapy was conducted. Within patient changes (post–pre IAEP therapy) in fluid loss, hemodynamics, patient-reported dyspnea, and serum biomarkers were assessed using Wilcoxon signed-rank testing. Of 21 enrolled patients, 18 received Aortix therapy. Mean ± SD patient age was 60.3 ± 7.9 years. The median left ventricular ejection fraction was 22.5% (25th-75th percentile: 10.0%-53.5%); 27.8% had a left ventricular ejection fraction ≥50%. Pre-therapy, patients received 8.7 ± 4.1 days of loop diuretic agents and 44% were on inotropes. Pump therapy averaged 4.6 ± 1.6 days, yielding net fluid losses of 10.7 ± 6.5 L (P < 0.001) and significant (P < 0.01) reductions in central venous pressure (change from baseline: −8.5 mm Hg [25th-75th percentile: −3.5 to −10.0 mm Hg]), pulmonary capillary wedge pressure (−11.0 mm Hg [25th-75th percentile: −5.0 to −14.0 mm Hg]), and serum creatinine (−0.2 mg/dL [25th-75th percentile: −0.1 to −0.5 mg/dL]) with improved estimated glomerular filtration rate (+5.0 mL/min/1.73 m2 [25th-75th percentile: 2.0-9.0 mL/min/1.73 m2]) and patient-reported dyspnea score (+16 [25th-75th percentile: 3-37]). Dyspnea scores, natriuretic peptides, and renal function improvements persisted through 30 days. This pilot study of patients with ADHF, persistent congestion, and worsening renal function due to CRS supports the potential for safely achieving decongestion using IAEP therapy. These initial promising results provide the basis for future randomized clinical trials of this novel pump. (An Evaluation of the Safety and Performance of the Aortix System for Intra-Aortic Mechanical Circulatory Support in Patients with Cardiorenal Syndrome [The Aortix CRS Pilot Study]; NCT04145635)
Corrigendum to “Is exposure to chemical pollutants associated with sleep outcomes? A systematic review” [Sleep Med Rev 70 (2023) 101805]
Authors: Danielle A. Wallace, Jayden Pace Gallagher, Shenita R. Peterson, Seyni Gueye-Ndiaye, Kathleen Fox, Susan Redline, Dayna A. Johnson
Journal: Sleep Medicine Reviews (2023)
Prevalence of tree nut allergy in Europe: A systematic review and meta‐analysis
Authors: Giulia C. I. Spolidoro, Daniil Lisik, Sungkutu Nyassi, Athina Ioannidou, Mohamed Mustafa Ali, Yohannes Tesfaye Amera, Graciela Rovner, Ekaterina Khaleva, Carina Venter, Ronald van Ree, Margitta Worm, Berber Vlieg‐Boerstra, Aziz Sheikh, Antonella Muraro, Graham Roberts, Bright I. Nwaru
Journal: Allergy (2023)

Abstract In 2014, the European Academy of Allergy and Clinical Immunology (EAACI) published the first systematic review that summarized the prevalence of food allergy (FA) and food sensitization in Europe for studies published 2000–2012. However, only summary estimates for tree nut allergy (TNA) were feasible in that work. In the current update of that systematic review, we summarized the prevalence of tree nut allergy/sensitization to individual tree nuts. Six databases were searched for relevant papers published 2012–2021 and 17 eligible studies were added to the 15 studies already identified between 2000 and 2012, giving a total of 32 studies. Of the investigated tree nuts, meta‐analysis was possible for hazelnut, walnut, almond, and in few cases, for cashew, and Brazil nut. The lifetime self‐reported prevalence was 0.8% (95% CI 0.5–1.1) for hazelnut and 0.4% (0.2–0.9) for walnut. The point self‐reported prevalence was 4.0% (2.9–5.2) for hazelnut, 3.4% (2.0–4.9) for Brazil nut, 2.0% (1.1–2.9) for almond, and 1.8% (1.1–2.5) for walnut. Point prevalence of food challenge‐confirmed TNA was 0.04% (0.0–0.1) for hazelnut and 0.02% (0.01–0.1) for walnut. Due to paucity of data, we could not identify any meaningful and consistent differences across age groups and European regions.
Reply to Esquinas <i>et al.</i>
Authors: Maxime Patout, Léa Razakamanantsoa, Rebecca D’Cruz, Gill Arbane, Thomas Similowski, Nicholas Hart, Patrick B. Murphy
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Reply to: Outcome and Cognition in Home Noninvasive Ventilation: A More Decisive Factor?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Harmonization of outcomes in epidermolysis bullosa: report of the Core Outcome Sets for Epidermolysis Bullosa (COSEB) kick-off meeting
Authors: Eva W H Korte, Phyllis I Spuls, Peter C van den Akker, Dimitra Kiritsi, Martin Laimer, Anna M G Pasmooij, Rainer Riedl, Elizabeth Vroom, Verena Wally, Tobias Welponer, Maria C Bolling
Journal: British Journal of Dermatology (2023)

The COSEB kick-off meeting was organized in April 2023, and highlighted the stakeholder perspectives on the unmet and urgent need to work towards reasonable harmonization of outcome measurement in epidermolysis bullosa (EB) by developing core outcome sets for the different EB types. Standardized and uniform outcome assessment holds great promise to reduce selective reporting, improve the comparability and pooling of treatment outcomes, and enhance the efficacy of future research in EB.
Seeing the whole elephant: designing ‘one health’ governance to fight antimicrobial resistance
Authors: Ian Brunskill, Deborah S. Somanader, Maureen Perrin, Herman W. Barkema, Sean Hillier, Suzanne Hindmarch, Ed Topp, Jeffrey Scott Weese, Gerard D. Wright, Andrew M. Morris
Journal: Clinical Microbiology and Infection (2023)
Bone marrow granulomatous reaction to silicone from breast implants
Authors: Gillian Horne, Ryan Rodgers, Mike Leach, Barbara J. Bain
Journal: American Journal of Hematology (2023)

Silicone lymphadenopathy occurs following migration of silicone particles through the lymphatic system to regional nodes and more distal extranodal sites as a consequence of implant rupture or “gel bleed”. This silicone migration and tissue deposition with granulomatous reaction may cause systemic symptoms which can mimic lymphoma – fatigue, fever, and sweats. It is an important condition to be aware of and to consider in the context of bone marrow granulomatosis. The authors declare no conflicts of interest.